Amino substituted acylthio cephalosporins

ABSTRACT

Amino substituted acylthio cephalosporins of the general formula   wherein R is hydrogen, lower alkyl, aralkyl, tri(lower alkyl)silyl, tri(lower alkyl)stannyl, a salt forming ion or the group   R1 is hydrogen, lower alkyl, aryl or certain heterocyclic groups; R2 and R3 each is hydrogen, lower alkyl or phenyl R4 is lower alkyl, aryl or aralkyl; R5 is hydrogen or lower alkyl; R6 is hydrogen or lower alkyl; or together R5 and R6 complete certain nitrogen heterocyclics; X is hydrogen, hydroxy, azido, lower alkanoyloxy, lower alkoxy, lower alkylthio, lower alkylthiadiazolythio, the radical of a nitrogen base, or together X and R represent a bond linking carbon and oxygen in a lactone ring; and n is 1, 2 or 3; are useful as antibacterial agents.

United States Patent [1 1 Treuner et al.

[ 1 AMINO SUBSTITUTED ACYLTHIO CEPl-IALOSPORINS {75] Inventors: Uwe D.Treuner; Hermann Breuer,

both of Regensburg, Germany [73] Assignee: E. R. Squibb & Sons, Inc.,

Princeton, NJ.

[22] Filed: Mar. 5, 1973 i[21] App]. N0.: 337,806

[52] US. Cl. 260/243 C; 424/246 [51] Int. Cl C07d 99/24 [58] Field ofSearch 260/243 C [56] References Cited UNITED STATES PATENTS 3,74L9626/1973 Brever 260/243 C Primary Examiner-Nicholas S. Rizzo Attorney,Agent, or Firm-Lawrence S. Levinson; Merle J. Smith \[57] ABSTRACT Aminosubstituted acylthio cephalosporins of the general formula [451 July29,1975

wherein R is hydrogen, lower alkyl, aralkyl, tri(lower alkyl)silyl,tri(lower alkyl)stannyl, a salt forming ion or the group R is hydrogen,lower alkyl, aryl or certain heterocyclic groups; R and R each ishydrogen, lower alkyl or phenyl R is lower alkyl, aryl or aralkyl; R ishydrogen or lower alkyl; R; is hydrogen or lower alkyl; or together Rand R complete certain nitrogen heterocyclics; X is hydrogen, hydroxy,azido, lower alkanoyloxy, lower alkoxy, lower alkylthio, loweralkylthiadiazolythio, the radical of a nitrogen base. or together X andR represent a bond linking carbon and oxygen in a lactone ring; and n isl. 2 or 3; are useful as antibacterial agents.

9 Claims, No Drawings AMINO SUBSTITUTED ACYLTHIO CEPHALOSPORINS SUMMARYOF THE INVENTION This invention relates to newaminoacylthiocephalosporins of the formula R represents hydrogen, loweralkyl, aralkyl, tri(lower alkyl)silyl, tri(lower alkyl)stannyl, a saltforming ion or the group R representshydrogen, lower alkyl, aryl orcertain heterocyclic groups; R and R each is hydrogen, lower alkyl orphenyl; R represents lower alkyl, aryl or aralkyl; R is hydrogen orlower alkyl; R is hydrogen or lower alkyl or R and R together completecertain nitrogen heterocyclics and n is l, 2 or 3. Xis hydrogen,hydroxy, azido, lower alkanoyloxy, lower alkoxy, lower alkylthio, loweralkylthiadiazolylthio, the radical of a nitrogen base, or together X-andRfrepresent a bond linking carbon and oxygen in a lactone ring.

The preferred members within each group are as follows: R is hydrogen,alkali metal or especially hydrogen, methyl, pivaloyloxy, sodium orpotassium; R is hydrogen, phenyl, thienyl, fury] or. isothiazolyl,especially hydrogen or 'phenyl; R and R each is hydrogen or loweralkyl','especially each is hydrogen, and methyl or ethyl when one orboth is lower alkyl; R is lower alkyl, preferably methyl or t-butyl; Rand R each is lower alkyl; n is l or 2, especially 1; and X ispreferably hydrogen or acetoxy.

DETAILED DESCRIPTION OF THE INVENTION The various groups represented bythe symbols have the meanings defined below and these definitions areretained throughout this specification.

The lower alkyl groups are straight or branched chain hydrocarbonradicals having one to eight carbons in the chain, for example, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl or the like.The lower alkoxy and lower alkylthio groups include similar radicals.

The aryl groups are phenyl and simply substituted phenyl having one tothree substituent groups. This includes phenyl and simply substitutedphenyl bearing one to three substituents R1 (Preferably only one), suchas the halogens (chlorine and bromine -being preferred), lower alkylgroups such as those defined above, lower alkoxy groups, hydroxy orcarboxy. In the case of the last two named substituents there ispreferably only one, especially in the para position of the phenyl.Illustrative are phenyl, 0-, mand p-chlorophenyl, o-, mandp-bromophenyl, 3,4-dichlorophenyl, 3,5- dibromophenyl, o-, mand p-tolyl,p-methoxyphenyl, 3,4,5-trimethoxyphenyl, p-hydroxyphenyl, pcarboxyphenyland the like.

The aralkyl groups include phenyl and phenyl attached to a lower alkylgroup, including substituted phenyl rings,all as defined above.Illustrative are benzyl, o-, mor p-chlorobenzyl, o-, mor p-bromobenzyl,o-, m- I or p' methylbenzyl, phe'nethyl, pchlorophenethyl,3,5-diethylbenzyl, 3,4,5- trichlorobenzyl and the like.

The lower alkanoyloxy groups represented by X include the acyl group ofacid esters. The lower alkano'yl radicals are the acyl radicals of lowerfatty acids containing alkyl radicals of the type described above. Thelower alkanoyloxy groups include, for example, acetoxy, propionyloxy,butyryloxy and the like. X also represents the radical of an amine,e.g., a lower alkylamine like methylamine, ethylamine,dimethylamine,triethylamine, phenyl-lower alkylamine like dibenzylamine,

and pyridine and quinoline quaternaries like pyridin-,

ium, l-quinolinium, l-picolinium, etc. X and R may also join together,as indicated above, to form a bond linking carbon ando rygen in alactone ring.

.The heterocyclic groups represented by R are pyridyl, thienyl, furyland isothiazolyl, as well as these heterocyclics with one or two of thesubstituents (R lhalo, lower alkyl (particularly methyl and ethyl),lower alkoxy (particularly methoxy and ethoxy) or phenyl. R and Rtogether with the nitrogen to which they are attached may also form aheterocyclic, i.e., piperidino, morpholino, thiamorpholino or piperazinoand these too may bear one or two of the substituents (R re ferred toabove.

The .salt forming ions represented by .R are metal ions, e.g.,:aluminum, alkali metal ions such as sodium or potassium, alkaline earthmetal ions such as calcium or magnesium;or an amine salt ion, of which anumber are known for this purpose, for example, phenyl-lower alkylamineslike 5 dibenzylamine, N,N- diben'zylethylenediamine, lower alkylamineslike methylamine, triethylamine, procaine, lower alkylpiperidines likeN-ethylpiperidine, etc. The ester forming tri(lower alkyl)silyl andtri(lower alkyl)stannyl groups include, for example, trimethylsilyl,triethyl'silyl, tri-nbutylstannyl and the like.

The new acylthiocephalosporins of the invention are produced by reactinga 7-aminocephalosporanic acid compound of formula II [which includesparticularly 7-aminocephalospo ranic acid (7-ACA and 7-amino-3-desacetoxycephalosporanic acid (7-ADCA)], or an activated derivativethereof, of the formula with an acid of the formula The activatedderivatives refered to include, for example, the reaction product withan anhydride forming reagent such as ethylchloroformate, benzoylchloride, pivaloyl chloride, etc., or with bis-imidazolecarbonyl,dicyclohexylcarbodiimide, p-nitrophenol or the like.

The reaction between the 7-aminocephalosporanic acid compound and theacid may be effected, for example, by dissolving or suspending thelatter in an inert organic solvent such as chloroform, methylenechloride, dioxane, benzene or the like, and adding, at about roomtemperature or below, about an equimolar amount of an anhydride formingreagent, e.g., ethyl chloroformate, benzoylchloride or the like, orother activating compound such as dicyclohexylcarbodiimide, along with asalt forming organic base, such as triethylamine, pyridine or the like,followed, after an interval, by the addition of the7-aminocephalosporanic acid compound. The product of the reaction isthen isolated by conventional procedures, e.g., by concentration orevaporation of the solvent. Other known methods involving mixedanhydrides, activated esters or amides, isoxazolium salts, etc. may alsobe utilized.

When R is the acyloxymethyl group with a compound of the formulaR]CH-CO-NH( |IH2 I N CH-CH2-X hell c/ l 0-0: H (VI) 0 or derivativethereof, in a solvent such as dimethylformamide. Me represents a metal,hal is halogen, preferably chlorine or bromine and all the other symbolsare the same as above.

The acid of formula IV and the salt of formula V are produced as followsaccording to the generally known method:

An amino acid of the formula is treated with a halogenated compound ofthe formula (Vlll) thereby obtaining a compound of the formula X R2 CH,

N C).,--CoocooC-CH RG 1 l R, C H

Treatment of this product with hydrogen sulfide in pyridine yields acompound of the formula The intermediate of formula X is then convertedto the alkali metal salt, e.g., with potassium methoxide to obtain aproduct of the formula which corresponds to the product of formula V.When this salt is treated with a halo acid of the formula hal in asolvent such as dimethylformamide the acid of formula II] is obtained.

See Bonner, Jour. Org. Chem. 33, 1831 (l968). See also US. Pat. No.3,264,337, Aug. 2, 1966.

Further process details are also provided in the illustrative examples.

Certain of the compounds of this invention may exist in differentoptically active forms. The various stereoisomeric forms as well as thediastereoisomeric mixtures are within the scope of the invention.

The compounds of this invention have a broad spectrum of antibacterialactivity against both gram positive and gram negative organisms such asStaphylococcus aureus, Salmonella schottmuelleri, Pseudomonasaerugiphenylacetamido)cephalosporanic acid and 0.8 g. (5 mmol.) of(dimethylamino)thioacetic acid S-potassium salt in 20 ml. ofdimethylformamide are stirred for 30 minutes at room temperature, thenpoured into ice nosa, Proteus vulgaris, Escherichia coli and Streptococ-5 water and extracted with 3 X 50 ml. of ethyl acetate. cus pyogenes.They may be used an antibacterial agents The organic phase is dried andthe solvent driven off to in a prophylactic manner, e.g., in cleaning ordisinfectgive DL-7-[2-[ [(dimethylamino)acetylJthio1-2- ingcompositions, or otherwise to combat infectionsphenylacetamido]cephalosporanic acid, m.p. 141. due to organisms such asthose named above, and in general may be utilized in a manner similar tocephalo- 10 thin andf gather lcelphalosprprinsl. For lpxample, a con?EXAMPLE 2 poun o ormu a or a p ysio ogica y acceptable sa t I thereofmay be used in various animal species in an7'[2"[[(dlmethylanzmo)acetymhlghcetamldolceph' amount of about 1 to 200mg/kg., daily, orally or parena osporamc terally, in single or two tofour divided doses to treat in- By substituting 2 g. (5 mmol.) of7-(2-bromo-2- fections of bacterial origin, e.g., 5.0 mg./kg. in mice.phenylacetamido)cephalosporanic acid in the proce- Oral forms giveprompt high blood-levels which are dure of Example 1, 7-[2- maintainedfor relatively long periods.[[(dimethylamino)]acetyl]thio]acetamido]cephalos- Up to about 600 mg. ofa compound of formula I or poranic acid, m.p. 128, is obtained. aphysiologically acceptable salt thereof may be incorporated in an oraldosage form such as tablets, capsules or elixirs or in an injectableformin a sterile aqueous EXAMPLE 3 vehicle prepared according toconventional pharma- DL 7 [[(dimethy]amino)aety]]thio] 2 ceutlcalpractlce- I phenylacetamido]-3-desacetoxycephalosporanic acid They mayalso be used in cleaning or d sinfecting y Substituting 7 (2 bromo zphenylacetamido) 3 f gi g g i aggg t sgi g 6 g 322 g;desacetoxycephalosporanic acid for the 7-(2-bromo-2- 0 yphenylacetamido)cephalosporanic acid in the proceof such compoundsadmixed vvlth, suspended or d1sdure of Example 1 solved in conventionalinert dry or aqueous carriers for ylaminonacetyl1thio] 2phe,ny]acetamid01 apphcatlmi washmg or spraymglThey are also use-3-desacetoxycephalosporanic acid is obtained. ful as nutrmqnalSupplements feeds The potassium salt is obtained by treating the freeThe following examples are illustrative of the invenacid with anequivalent amount of potassium carbom tion. All temperatures are on theCentigrade scale. Adate dmonal vanatpns may b grodllced m same i Thefollowing additional products having the formula ner by appropriatesubstitution n the starting material. (c) in the table are obtained bythe procedure of Exam;

EXAMPLE 1 pie 2 by substituting for the 7-a-(bromophenylacetamido)cephalosporanic acid, the 1 :aigg g ggigz figglfgg3222; starting material (a), and for the (dimethylamino)thip e v p p40. oacetic acid salt, the starting material (b) with the sub- 2.35 g.(5 mmol.) of 7-(2-br0mO-2 stituents indicated in the table:

TABLE 5 lR C H CO-NH--| R2 5 la. N 01 --x k-s-C-(ln -N RCHCO-NH CH 6 \CH0/ 2 R. l 0 2 T2 R fi-N\ //C-CH,X

- SC(C),,N O C ll II R. I

0 R (If-OR Example R R, R2 R3 R5 R n X 4 K H H H c H, C2H5 1 H .5 C211,CH H H H CH 1 0H 6 H CHH H H CH3 CH3 1 pyridinium v -cH.0%-CH CH.3; ca.H H cH, ca, 1 ococH,

ll 8 CH2OCC5H,, 4-clc H, H H C H, C H,, l OCOCH 9 K a )2 a a CH3 H CH3CH3 1 H l0 H C H, H H. C C H 2 f? s S CH What is claimed is:

l. A compound of the formula 60 wherein R is hydrogen, lower alkyl,phenyl-lower alkyl,

tri(lower alkyl)silyl, tri(lower alkyl)stannyl,

O CH OE-R R, is phenyl, R and R each is hydrogen or lower alkyl,

R R and R each is lower alkyl, n is l or 2 and X is hydrogen or acetoxy.

3. A compound as in claim 1 wherein R, is phenyl.

4. A compound as in claim 3 wherein R, R- R and X each is hydrogen, Rand R, each is lower alkyl.

5. A compound as in claim 4 wherein each lower alkyl group is methyl andn is l.

6. A compound as in claim 3 wherein R, R, and R, each is hydrogen, R andR each is lower alkyl and X is acetoxy.

7. A compound as in claim 6 wherein each lower alkyl group is methyl andn is l.

8. A compound as in claim 1 wherein R, R R, and R each is hydrogen, Rand R each is lower alkyl and X is acetoxy.

9. A compound as in claim 8 wherein each lower alkyl group is methyl andn is l.

I l k

1. A COMPOUND OF THE FORMULA
 2. A compound as in claim 1 wherein R ishydrogen, alkali metal, or
 3. A compound as in claim 1 wherein R1 isphenyl.
 4. A compound as in claim 3 wherein R, R2, R3 and X each ishydrogen, R5 and R6 each is lower alkyl.
 5. A compound as in claim 4wherein each lower alkyl group is methyl and n is
 1. 6. A compound as inclaim 3 wherein R, R2 and R3 each is hydrogen, R5 and R6 each is loweralkyl and X is acetoxy.
 7. A compound as in claim 6 wherein each loweralkyl group is methyl and n is
 1. 8. A compound as in claim 1 wherein R,R1, R2 and R3 each is hydrogen, R5 and R6 each is lower alkyl and X isacetoxy.
 9. A compound as in claim 8 wherein each lower alkyl group ismethyl and n is 1.